NIDA has had a long-standing mission to determine the impact of chronic stress on substance use, abuse, and addiction. This application addresses this important objective in multiple, innovative ways. In particular, we focus on late adolescents with histories of experiencing child maltreatment, a severe and chronic stressor contributing to high risk for maladaptation, psychopathology, and substance use and abuse across the life course. Although numerous studies have identified a linkage between child maltreatment and substance use in adolescence and adulthood, the developmental mechanisms through which the experience of the chronic stress of child maltreatment results in substance use and abuse have received only minimal attention. Child maltreatment is known to impair both biological and psychological systems, and it is essential to investigate how these developmental consequences of child abuse and neglect contribute to the emergence of substance abuse outcomes. In the present application, we're seeking a renewal of our previous investigation of a diverse cohort of preadolescent maltreated and nonmaltreated children studied during a period when there is minimal substance use normatively. We propose to follow-up this sample of children in late adolescence/emerging adulthood, a period when substance abuse normatively escalates. We will capitalize on the solid developmental foundation acquired in the original study, which obtained an extensive assessment of multilevel influences (socio- emotional, interpersonal, family relational, social contextual, personality, psychopathology, attentional, neurocognitive, and neuroendocrine) in maltreated and nonmaltreated children. The multilevel assessment of diverse domains will be continued in the present application. We also will include genetic sampling in order to investigate the potential of protective vs. risk promoting influences of genetic variants on late adolescent substance abuse outcomes and differential effects dependent on exposure to child maltreatment. We will conduct diverse multilevel assessments with the late adolescents, as well as obtain perspectives on the late adolescent's functioning from caregivers and best friends. Assessing the effects of chronic stress on stress-sensitive systems at earlier, more distal periods of development, as well as the capacity to integrate both distal and proximal adaptations to chronic stress in late adolescence has the potential to greatly expand understanding of the multilevel impact of chronic stress on drug abuse. This research will have important implications for public health. In addition to advancing knowledge regarding the multilevel developmental roots of substance use and abuse, the research will provide important direction for prevention and intervention strategies. Given that multiple pathways from child maltreatment to substance abuse are likely to be identified, insights into different intervention targets will be elucidated.